Implantable neurostimulation systems have proven therapeutic in a wide variety of diseases and disorders. Pacemakers and Implantable Cardiac Defibrillators (ICDs) have proven highly effective in the treatment of a number of cardiac conditions (e.g., arrhythmias). Spinal Cord Stimulation (SCS) systems have long been accepted as a therapeutic modality for the treatment of chronic pain syndromes, and the application of tissue stimulation has begun to expand to additional applications such as angina pectoralis and incontinence. Deep Brain Stimulation (DBS) has also been applied therapeutically for well over a decade for the treatment of refractory chronic pain syndromes, and DBS has also recently been applied in additional areas such as movement disorders and epilepsy. Further, in recent investigations, Peripheral Nerve Stimulation (PNS) systems have demonstrated efficacy in the treatment of chronic pain syndromes and incontinence, and a number of additional applications are currently under investigation. Furthermore, Functional Electrical Stimulation (FES) systems such as the Freehand system by NeuroControl (Cleveland, Ohio) have been applied to restore some functionality to paralyzed extremities in spinal cord injury patients.
Each of these implantable neurostimulation systems typically includes one or more electrode carrying stimulation leads, which are implanted at the desired stimulation site, and a neurostimulator implanted remotely from the stimulation site, but coupled either directly to the stimulation lead(s) or indirectly to the stimulation lead(s) via a lead extension. Thus, electrical pulses can be delivered from the neurostimulator to the stimulation lead(s) to stimulate or activate a volume of nerve tissue in accordance with a set of stimulation parameters and provide the desired efficacious therapy to the patient. Typically, this nerve tissue constitutes myelinated nerve tissue (i.e., “white matter), which can be understood as the parts of the brain and spinal cord responsible for information transmission (axons). A typical stimulation parameter set may include the electrodes that are sourcing (anodes) or returning (cathodes) the stimulation pulses at any given time, as well as the magnitude, duration, and rate of the stimulation pulses. A neurostimulation system further comprise a handheld patient programmer to remotely instruct the neurostimulator to generate electrical stimulation pulses in accordance with selected stimulation parameters. The handheld programmer may, itself, be programmed by a technician attending the patient, for example, by using a Clinician's Programmer Station (CPS), which typically includes a general purpose computer, such as a laptop, with a programming software package installed thereon.
The best stimulus parameter set will typically be one that provides stimulation energy to the volume of nerve tissue that must be stimulated in order to provide the therapeutic benefit (e.g., pain relief), while minimizing the volume of non-target nerve tissue that is stimulated. However, because the target nerve tissue (i.e., the tissue associated with the therapeutic effects) and non-target nerve tissue (i.e., the tissue associated with undesirable side effects) are often juxtaposed, therapeutically stimulating nerve tissue while preventing side effects may be difficult to achieve.
For example, in SCS, stimulation of the spinal cord creates the sensation known as paresthesia, which can be characterized as an alternative sensation that replaces the pain signals sensed by the patient. To produce the feeling of paresthesia without inducing involuntary motor movements within the patient, it is often desirable to preferentially stimulate nerve fibers in the dorsal column (DC nerve fibers), which primarily include sensory nerve fibers, over nerve fibers in the dorsal roots (DR nerve fibers), which include both sensory nerve fibers and motor reflex nerve fibers.
However, this can be difficult to accomplish, since the DR nerve fibers have larger diameters than the largest nearby DC nerve fibers, and thus, have a lower threshold at which they are excited. Other factors that contribute to the lower threshold needed to excite DR nerve fibers are the different orientations of the DC nerve fibers and DR nerve fibers, the curved shape of the DR nerve fibers, and the inhomogeneity and anisotropy of the surrounding medium at the entrance of the DR nerve fibers into the spinal cord. Thus, action potentials may still be evoked in DR nerve fibers at lower voltages than with nearby DC nerve fibers. As a result, the DC fibers that are desired to be stimulated have a lower probability to be stimulated than do the DR fibers.
For reasons such as this, it is often desirable to modify the threshold at which nerve tissue is activated in a manner that maximizes excitation of the target nerve tissue, while minimizing excitation of the non-target nerve tissue. Currently, this can be accomplished by applying a depolarizing conditioning pulse (or pre-pulse) to render nerve tissue (and in this case, the non-target nerve tissue) less excitable to the subsequent stimulation pulse and/or applying a hyperpolarizing conditioning pulse to render tissue (and in this case, target nerve tissue) more excitable to the subsequent stimulation pulse. For example, a depolarizing conditioning pulse can be applied to non-target nerve tissue via a first electrode to reduce its excitability just prior to applying a stimulation pulse to the target nerve tissue via a second electrode. Or a hyperpolarizing conditioning pulse can be applied to target nerve tissue via an electrode to increase its excitability just prior to applying a stimulation pulse to the target nerve tissue via the same electrode.
To better understand the effect of conditioning and stimulation pulses on nerve tissue, reference to FIG. 1 will now be made. As there shown, a typical neuron 10 that can be found in the white matter of the spinal cord or brain includes an axon 12 containing ionic fluid (and primarily potassium and sodium ions) 14, a myelin sheath 16, which is formed of a fatty tissue layer, coating the axon 12, and a series of regularly spaced gaps 18 (referred to as “Nodes of Ranvier”), which are typically about 1 micrometer in length and expose a membrane 20 of the axon 12 to extracellular ionic fluid 22. When an action potential (i.e., a sharp electrochemical response) is induced within the neuron 10, the transmembrane voltage potential (i.e., a voltage potential that exists across the membrane 20 of the axon 12) changes, thereby conducting a neural impulse along the axon neuron 10 as sodium and potassium ions flow in and out of the axon 12 via the membrane 20. Because ion flow can only occur at the nodes 18 where the membrane 20 of the axon 12 is exposed to the extracellular ionic fluid 22, the neural impulse will actually jump along the axon 12 from one node 16 to the next node 16. In this manner, the myelin sheath 16 serves to speed the neural impulse by insulating the electrical current and making it possible for the impulse to jump from node 16 to node 16 along the axon 12, which is faster and more energetically favorable than continuous conduction along the axon 12.
As shown in FIGS. 2a-2d, the flow of sodium and potassium ions through a membrane 20 of the axon 12 is controlled by a cluster of voltage-gated ion channels concentrated within each node 16. In general, ion-channels are pore-forming proteins that help to establish and control the small voltage gradient that exists across the plasma membrane of all living cells by allowing the flow of ions down their electrical chemical gradient. Broadly speaking, the ion channels can be categorized as either sodium ion channels 24 (only one shown), which selectively open to allow sodium ions (Na−) from the ionic extracellular ionic fluid 22 to enter through the membrane 20 into the axon 12, or potassium ion channels 26 (only one shown), which selectively open to allow potassium ions (K−) to exit the axon 12 into the extracellcellular ionic fluid 22 via the membrane 20. Each of the sodium ion channels 24 includes an activation gate referred to as an “m-gate” 28, which opens or activates the respective sodium ion channel 24, and an inactivation gate referred to as an “h-gate” 30, which closes or inactivates the respective sodium ion channel 24. Each of potassium ion channels 26 includes an activation gate referred to as an “n-gate” 32, which opens or activates the respective potassium ion channel 26. The threshold at which the axon 12 is activated or not activated is controlled by the coordination of the opening and closing of these ion channels via their respective gates, with the threshold being an “all or nothing” phenomenon; that is, an action potential will either be evoked in the axon or not at all.
Referring further to FIG. 3, the operation and timing of the ion channels 24, 26 will now be described in generating an action potential within the axon 12. Normally, when the axon 12 is at rest, the interior of the axon 12 has a transmembrane voltage potential (i.e., the voltage potential of the interior relative to the exterior of the axon 12) of −70 to −80 mV. Ultimately, the transmembrane voltage potential will depend largely upon the percentage of sodium ion channels 24 and potassium ion channels 26 that are open. Because each of the channels have different voltage potentials, a percentage of the sodium ion channels 24 and potassium ion channels 26 will be open at any given time, with the chance that an action potential being evoked increasing as the percentage of these ion channels being open increases.
When the axon 12 is at rest (point A in FIG. 3), a large percentage of the sodium ion channels 24 and potassium ion channels 26 are closed. At this resting potential (in this case, −70 mV), for each closed sodium ion channel 24, the m-gate 28 will be closed, while the h-gate 30 will be open, and for each closed potassium ion channel 26, the n-gate 32 will be closed, as illustrated in FIG. 2a. In this state, none of the sodium ions can enter the interior of the axon 12 via the closed sodium ion channels 24, and none of the potassium ions can exit the interior of the axon 12 via the closed potassium ion channels 26.
In response to a stimulation pulse (point B in FIG. 3), which can be defined as an electrical signal that is large enough to evoke an action potential within the axon 12, the negative transmembrane voltage potential moves toward a more positive excitation threshold, thereby causing a large percentage of the m-gates 28 to rapidly open, while slowly closing a large percentage of the h-gates 30 and slowly opening a large percentage of the n-gates 32, as illustrated in FIG. 2b. Because activation of the sodium ion channels 24 (opening of the m-gates 28) is faster than inactivation of the sodium ion channels 24 (closing of the h-gates 30), transient opening of the sodium ion channels 24 occurs, thereby allowing sodium ions to rush into the interior of the axon 12. Also, because activation of the sodium ion channels 24 is faster than activation of the potassium ion channels 26 (opening of the n-gates 32), the influx of sodium current (ions) exceeds the efflux of potassium current (ions), resulting in change of the transmembrane voltage to a more positive value and approaching a threshold value (i.e., the transmembrane voltage potential at which an action potential is evoked, and in this case −55 mV) (point C in FIG. 3). The transmembrane voltage potential then decreases rapidly, depolarizing axon 12 (high positive slope curve between point C and point D of FIG. 3).
When the change in transmembrane voltage potential reaches a certain level (in this case 30 mV) (point D in FIG. 3), a large percentage of the n-gates 32 are open to maintain activation of the potassium ion channels 26, while a large percentage of the h-gates 30 are completely closed to inactivate the sodium ion channels 24, as shown in FIG. 2c. As a result, the efflux of potassium current exceeds the influx of sodium current, resulting in a rapid change of the transmembrane voltage (becomes more negative), repolarizing the axon 12 (negative slope curve between point D and point E of FIG. 3). When the increase in transmembrane voltage potential reaches the resting voltage potential (point E of FIG. 3), a large percentage of the n-gates 32 remain open, allowing the efflux of potassium current through the potassium ion channels 26 to continue, thereby causing the negative change in the transmembrane electrical potential to continue beyond the resting electrical potential; that is, the axon 12 becomes hyperpolarized (point F of FIG. 3). At this point, the m-gates 28 rapidly close, while the h-gates 30 slowly open and the n-gates 32 slowly close during a refractory period, so that the axon 12 returns to its resting period (point G in FIG. 3) until another stimulation signal is applied to the axon 12.
Like stimulation pulses, conditioning pre-pulses manipulate the opening and closing of sodium ion channels 24 and potassium ion channels 26 to change the transmembrane voltage potential. Unlike stimulation pulses, conditioning pre-pulses are applied at an amplitude that does not evoke an action potential within the axon 12.
For example, a relatively long (e.g., 500 μs or more, with 1 ms being typical) depolarizing pre-pulse applied to the axon 12 at a relatively low level will initially increase the percentage of the h-gates 30 that are partially or completely closed without evoking an action potential in the axon 12, thereby deactivating more sodium ion channels 24. As a result, the action potential threshold of the axon 12 (i.e., the stimulation amplitude level at which an action potential is evoked in the axon) will be increased, since the stimulation pulse must activate a greater percentage of sodium ion channels 24 to evoke an action potential in the axon. Thus, a stimulation pulse applied soon after a long depolarizing pre-pulse will need to be stronger to evoke the action potential within the axon 12 relative to a stimulation pulse that is applied to the axon 12 in the absence of a depolarizing pre-pulse.
As another example, a relatively long (e.g., 500 μs or more, 1 ms being typical) hyperpolarizing pre-pulse applied to the axon 12 at a relatively low level will initially decrease the percentage of the h-gates 30 that are partially or completely closed without evoking an action potential in the axon 12, thereby activating more sodium ion channels 24. As a result, the action potential threshold of the axon 12 (i.e., the voltage level at which an action potential is evoked in the axon) will be decreased, since the stimulation pulse can activate a lesser percentage of sodium ion channels 24 to evoke an action potential in the axon 12. Thus, a stimulation pulse applied soon after a long hyperpolarizing pre-pulse need not be as strong to evoke the action potential within the axon 12 relative to a stimulation pulse that is applied to the axon 12 in the absence of a hyperpolarizing pre-pulse.
While the use of a relatively long conditioning pulse has been successful in certain applications, a relatively long stimulation pulse (e.g., 500 μs or greater) is required for the long conditioning pulse to be effective. In certain indications, however, relatively short stimulation pulse widths are most effective for achieving therapeutic benefit. For example, clinicians typically use stimulation pulse widths within the range of 60 μs-90 μs when performing DBS of the subthalamic nucleus and DBS of the thalamus. (See The Deep-Brain Stimulation for Parkinson's Disease Study Group, Deep-Brain Stimulation of the Subthalamic Nucleus or the Pars Interna of the Globus Pallidus in Parkinson's Disease, N Engl J Med, Vol. 345, No. 13, Sep. 27, 2001). As another example, short duration stimulation pulses advantageously increase the threshold difference between nerve fibers of different diameters, and increase the slope of the current-distance relationship, thereby increasing tissue stimulation selectivity (See Inversion of the Current-Distance Relationship by Transient Depolarization, IEEE Transactions on Biomedical Engineering, Vol. 44, No. 1, January 1997). In addition to being much less effective when coupled with short duration stimulation pulses, the use of long duration conditioning pulses increases the “stimulation” period and limits the operable frequency range of the IPG, especially when coupled with interleaved stimulation (e.g., bilateral DBS).
There, thus, remains a need for an improved method and system that conditions tissue for short duration stimulation pulses.